The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A

Lung epithelial cells and fibroblasts poorly express angiotensin-converting enzyme 2, and the study aimed to investigate the role of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on inflammation and epithelial–mesenchymal transition (EMT) in two lung cell lines and to understand the potential mechanism. Lung epithelial cells (BEAS-2B) and fibroblasts (MRC-5) were treated with the spike protein, then inflammatory and EMT phenotypes were detected by enzyme-linked immunosorbent assay, Transwell, and western blot assays. RNA-sequence and bioinformatic analyses were performed to identify dysregulated genes. The roles of the candidate genes were further investigated. The results showed that treatment with 1,000 ng/mL of spike protein in two lung cell lines caused increased levels of IL-6, TNF-α, CXCL1, and CXCL3, and the occurrence of EMT. RNA-sequence identified 4,238 dysregulated genes in the spike group, and 18 candidate genes were involved in both inflammation- and EMT-related processes. GADD45A had the highest verified fold change (abs), and overexpression of GADD45A promoted the secretion of cytokines and EMT in the two lung cell lines. In conclusion, the spike protein induces inflammation and EMT in lung epithelial cells and fibroblasts by upregulating GADD45A, providing a new target to inhibit inflammation and EMT.